The present invention relates to a method for preparing 6-methyl steroids.
The 6-methyl steroids producible according to this invention, especially those of the pregnane series, are known pharmaceuticals. Since the presence of the 6-methyl group frequently causes a considerable rise in efficacy in steroidal progestogens and corticoids, numerous efforts have been made in the past to provide methods of introducing this methyl group.
Thus, for example, megestrol acetate (17.alpha.-acetoxy-6-methyl-4,6-pregnadiene-3,20-dione) is utilized for the treatment of inoperable, metastasizing endometrial carcinoma, and medrogestone (6,17-dimethyl-4,6-pregnadiene-3,20-dione) is used for the treatment of menstrual disorders and premenstrual tension conditions.
Megestrol acetate is prepared according to a synthesis by Djerassi and Ringold [H. H. Ringold et al., J. Amer. Chem. Soc. 81: 3712 (1959)] in a multistage procedure by ketalizing 3.beta.-acetoxy-17.alpha.-hydroxy-5-pregnen-20-one, epoxidizing the thus-obtained 20-ketal on the .DELTA..sup.5 -double bond, and reacting the resultant 5,6.alpha.-epoxy-20-ethylenedioxy steroid with a methylmagnesium halide to form 6.beta.-methyl-5.alpha.-hydroxyketal, while also splitting off the 3.alpha.-acetoxy group during this step. After ketal cleavage and subsequent oxidation, 5.alpha.,17.alpha.-dihydroxy-6.beta.-methyl-3,20-diketopregnane is obtained yielding 6.alpha.-methyl-17.alpha.-hydroxyprogesterone while splitting off water and with inversion of the 6-methyl group. Acetylation on the C-17 leads to 6.alpha.-methyl-17.alpha.-acetoxyprogesterone, and subsequent dehydrogenation results in the desired .DELTA..sup.4,6 -dienone.
A newer synthesis [F. Schneider et al., Helv. Chim. Acta 56: 2396 (1973)] starts with 17.alpha.-acetoxyprogesterone, which is first blocked in the 3-position by a pyrrolidino group and then reacted with formaldehyde to form 6.beta.-hydroxymethylene-17.alpha.-acetoxyprogesterone. By splitting off water, the 6-exomethylene compound is obtained; the latter is isomerized with palladium/carbon/cyclohexane to form the desired 6-methyl-.DELTA..sup.4,6 -compound.
The synthesis described by Petrow or Kadamski [V. Petrow et al., Tetrahedron 21: 1619 (1965); ibid. 25: 1165 (1968); or G. M. Kadamski et al., Khim. Farm. Zh. 1979 (6) 63] proceeds likewise in a similar way. The starting compound here is also 17.alpha.-acetoxyhydroxyprogesterone which, after 3-enolizing with dimethylformamide in a Vilsmeier reaction, reacts to form the Schiff base. Hydrolysis yields the 6-formyl compound and, after reduction, the 6-hydroxymethylene compound. By means of a further hydrolysis, the 6-exomethylene compound is then obtained which is again isomerized to the desired 6-methyl-4,6-dienone.
All of these syntheses have the drawback in common that they proceed over a number of stages, thus naturally reducing the final yield of the desired 6-methyl-4,6-dienone compound.